Prostate cancer is the most commonly diagnosed cancer and the second most common cause of death from cancer in American men. Prostate cancer cells often initially rely on androgen (e.g., testosterone) for their growth and maintenance. Therefore, androgen withdrawal, by castration or through the use of an anti-androgenic drug, is a common treatment for prostate cancer. In many cases, however, prostate cancer patients develop androgen-independent prostate cancer so that androgen withdrawal treatment is no longer effective.
The complex process of prostate tumor growth and development involves multiple gene products. Therefore, it is important to identify genes involved in tumor development, growth, and androgen dependence, particularly those genes and gene products that can serve as targets for the diagnosis, prevention, and treatment of prostate cancer.
The present invention concerns diagnostic, therapeutic, and screening methods employing KIAA0101 (Genbank Accession No. D14657).
KIAA0101 is expressed in an androgen-responsive prostate cancer cell line LNCaP. In the presence of casodex, an anti-androgen, expression is decreased 3-fold. In contrast, KIAA0101 is constitutively expresssed in androgen-independent prostate cancer cells.
Because androgen is required for optimal growth and survival of androgen-responsive prostate cancer cells, genes such KIAA0101 whose expression is decreased in the presence of casodex, an anti-androgen, are potential therapeutic targets. An agent which decreases the expression or activity of KIAA0101 may slow the growth of, arrest the growth of, or kill prostate cancer cells, including androgen-independent prostate cancer cells. Moreover, because KIAA0101 is constitutively expressed by androgen-independent prostate cancer cells (e.g., CWR22R cells), it can be used to identify agents that may be useful for the treatment of androgen-independent prostate cancer.
For example, an agent which reduces the expression or activity of KIAA0101 may reduce the growth of androgen-independent prostate cancer or cause an androgen-dependent cancer to become androgen-dependent so that it can be treated with standard androgen withdrawal therapy. Of course, such an agent might also be useful for the treatment of an androgen-dependent prostate cancer.
Useful therapeutic agents can be identified using androgen-dependent prostate cancer cells (e.g., CWR22 cells) or androgen-independent prostate cancer cells (e.g., CWR22R cells) which express KIAA0101. The growth of such cells in the presence and absence of a test agent is measured (in the presence or absence of an androgen). Compounds which reduce cell growth, reduce KIAA0101 expression, or reduce KIAA0101 activity are potential therapeutic agents for the treatment of prostate cancer (e.g., androgen-independent prostate cancer)
Because KIAA0101 expression in androgen-sensitive prostate cancer cells is decreased in the presence of casodex, an anti-androgen, KIAA0101 expression or activity can serve as a marker for monitoring anti-androgen therapy. For example, KIAA0101 should not be expressed at a significant level in prostate cancer cells of patients undergoing anti-androgen therapy. An increase over time in KIAA0101 expression or activity in the prostate cancer cells of a patient undergoing anti-androgen therapy indicates that the therapy is becoming less effective. Such an increase can also indicate that the cancer is androgen-independent. In this and other assays of KIAA0101 expressioon, the measured level of KIAA0101 expression is preferably normalized to the expression level of a non-regulated (e.g., housekeeping) gene such as actin.
Thus, the invention also features diagnostic methods and prognostic methods which can be used to identify patients having or at risk for developing and androgen-independent prostate cancer. KIAA0101 polypeptides and nucleic acids can be used to identify cells exhibiting or predisposed to developing prostate cancer, thereby diagnosing individuals having, or at high risk for developing, an androgen-independent prostate cancer.
The above-described diagnostic methods permit one to predict whether a selected compound, e.g., an anti-androgenic compound, can be used to treat the prostate cancer. Importantly, this determination can be made on a patient by patient basis.
In the various methods of the invention, KIAA0101 expression can be measured at the mRNA or protein level. Alternatively, expression can be measured indirectly by measuring the activity of KIAA0101 protein.
In another aspect, the present invention provides a method for detecting the presence of KIAA0101 activity or expression in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of KIAA0101 activity such that the presence of KIAA0101 activity is detected in the biological sample.
In another aspect, the invention provides a method for treating prostate cancer by modulating the expression or activity of KIAA0101, the method comprising contacting a cell with an agent that modulates (inhibits or stimulates, preferably inhibits) KIAA0101 activity or expression such that KIAA0101 activity or expression in the cell is modulated. In one embodiment, the agent is an antibody that specifically binds to KIAA0101. In another embodiment, the agent modulates expression of KIAA0101 by modulating transcription, modulating mRNA splicing, or modulating mRNA translation. In yet another embodiment, the agent is a nucleic acid molecule having a nucleotide sequence that is antisense to the coding strand of KIAA0101.
In one embodiment, the methods of the present invention are used to treat a subject having a prostate cancer characterized by aberrant KIAA0101 protein activity or expression (e.g., constitutive expression in absence of an androgen or abnormally high expression in the presence of estrogen) by administering an agent which is a KIAA0101 modulator to the subject. The modulator can be a peptide, peptidomimetic, or small molecule, e.g., an organic molecule.
The present invention also provides a diagnostic assay for identifying whether a patient has or is at risk of developing prostate cancer by detecting the presence or absence of a genetic lesion or mutation in a KIAA0101 gene characterized by at least one of: (i) aberrant modification or mutation of a gene of the invention; (ii) mis-regulation of a gene of the invention (e.g., constitutive expression in the absence of androgen); and (iii) aberrant post-translational modification of a protein encoded by a gene of the invention.
In another aspect, the invention provides a method for identifying a compound for the treatment of prostate cancer (e.g., an androgen-independent prostate cancer or an androgen-dependent prostate cancer) by identifying a compound that binds to or modulates the activity of KIAA0101 protein. In general, such methods entail measuring a biological activity of KIAA0101 in the presence and absence of a test compound and identifying those compounds which alter the measured activity of KIAA0101.
The invention also features methods for identifying a compound which modulates the expression of KIAA0101 (at the mRNA or protein level) by measuring the expression of a KIAA0101 nucleic acid or protein in the presence and absence of a compound.
The present invention provides methods for detecting the presence of the activity or expression of a polypeptide of the invention in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of activity such that the presence of activity is detected in the biological sample.
Differential expression refers to both quantitative, as well as qualitative, differences in the expression pattern of a gene in tumor cells treated with a particular compound (e.g., casodex) and untreated tumor cells. A differentially expressed gene can be a target gene. A target gene is a differentially expressed gene involved in a disorder (e.g., prostate cancer) such that modulation of the level of target gene expression or of target gene product activity can act to prevent and/or ameliorate symptoms of the disorder (e.g., androgen-dependent or androgen-independent prostate cancer). Compounds that modulate the expression of the target gene or the activity of the target gene product can be used in the treatment or prevention of the disorder. Thus, compounds that modulate the expression of a prostate cancer target gene or the activity of the gene product of a prostate cancer target gene can be used in treatments to deter benign cells from developing into prostate cancer cells. Still further, compounds that modulate the expression of a prostate cancer target gene or the activity of the gene product of a prostate cancer target gene can be used to design a preventive intervention in pre-neoplastic cells in individuals at high risk for developing prostate cancer.
An androgen-dependent prostate cancer cell is a cell that requires androgen for continued cell division. Conversely, and androgen-independent prostate cancer cell is a cell that can continue to divide in the absence of androgen.
Other features and advantages of the invention will be apparent from the following detailed description and claims.